In the nervous system, excitatory neurotransmission markedly influences the expression of genes that are likely to be critical for long-term neuronal adaptive responses, including the maintenance phases of LTP and LTD. Thus, neurotransmitter-sensitive genes may be important substrates of complex neurobiological phenomena underlying learning and memory. The transcription factor CREB has been implicated in regulation of neurotransmitter-sensitive genes and the control of long-term neuronal adaptive responses in both invertebrates and vertebrates. Excitatory neurotransmitters stimulate the phosphorylation of CREB on a single transcriptional regulatory site, serine 133 (Ser133), and this phosphorylation event is critical for CREB-mediated transcription. However, a mammalian model system useful for determining the role of CREB in neurotransmitter signaling, or for identification of genes whose expression is CREB-dependent does not exist. A mouse containing a targeted mutation within the CREB gene exists, but this mouse expresses high levels of a functional CREB protein in brain and other tissues, and the neurons from these mice display neurotransmitter-sensitive, CREB-mediated transcription. The overall objective of the present proposal is to generate two transgenic mouse lines that are either deficient in CREB DNA binding activity or that express a mutant CREB protein that cannot be activated by phosphorylation. Since CREB-dependent transcription is likely to be important for aspects of nervous system development, we will employ new procedures to express our previously characterized dominant negative CREB transgenes exclusively in adult neurons under conditional fashion. These mice will form the basis for future experiments that will address the role of CREB and phosphorylation of CREB Ser133 in neurotransmitter regulation of gene expression, synaptic plasticity and, ultimately, complex neurobiological phenomena such as learning and memory. Moreover, mice deficient in CREB activity exclusively in adult neurons will provide a model system useful for identification of gene whose expression is dependent upon CREB.